Tetrahydroisoquinolines



United States Patent 1 3,420,818 TETRAHYDROISOQUINOLINES Hans0tt,'Convent Station, N.J., assignor to Sandoz, Inc., Hanover, NJ.

No Drawing. Continuation-impart of application Ser. No. 391,732, Aug.24, 1964. This application Feb. 20, 1967, Ser. No. 617,051

U.,S. Cl. 260239.3 36 Claims Int. Cl. C07d 53/06 ABSTRACT OF THEDISCLOSURE This application is a continuation-in-part of applicationSer. No. 391,732 filed Aug. 24, 1964, application Ser. No.

447,522'filed Apr. 12, 1965, application Ser. No. 477,975

filed Aug 6, 1965, and application Ser. No. 477,976 filed Aug. 6, 1965now all abandoned.

The invention provides pharmaceutically acceptabletetrahydroisoquinobenzodiazepinones of the formula wherein each of R andR is either, independently, a hydrogen atom (H); chloro (Cl); bromo(-Br); lower alkyl, e,g. methyl, ethyl, propyl and butyl; lower alkoxy,

e.g. methoxy, ethoxy, propoxy and butoxy; or, taken together,methylenedioxy (O CH O- 7 each of R and R is either a hydrogen atom (H)or lower alkyl, e.g. methyl, ethyl, propyl and butyl; R is either ahydrogen atom (H); lower alkyl, e.g. "methyl, ethyl, propyl, isopropyland butyl, preferably having from 1 to 4 carbon atoms; allyl; orpropargyl;

and X is either a hydrogen atom (H); halo (preferably -Cl or Br); nitro(NO amino (NH or trifluoromethyl (CF;.,); and N -oxides thereof. [Forthe N -oxides R and R are, preferably, either a hydrogen atom, loweralkoxy or, taken together, methylenedioxy; R is either hydrogen or loweralkyl; and X is, preferably, a hydrogen atom, chloro, bromo, nitro ortrifluoromethyL] The. key intermediates (compounds II) in the synthesisof Compound I,

3,420,818 Patented Jan. 7, 1969 Ice meaning, as it does throughout theinstant text unless otherwise specified,

are also within the scope of the present invention.

Intermediates II are prepared according to a number of differentreaction schemes either from known starting materials or from startingmaterials which are readily pre pared by the art-skilled according toknown procedures and from known materials. Exemplary reaction schemesare:

A R O=COR R NH l 5 R NH: X

III IV R (a) tosylate R (D) Bischler-Napieralski cyclizatiou H (c)saponification R I of tosylate 0:0 (d) reduction I -NH I X- N-R III VI11 O=CCl R I R e aim n apieras 1 111+ R? cyclization X NH (b) reductionVIII wherein R is either methyl or ethyl. (See Compounds IV and IX.)

Compounds I are prepared from the corresponding intermediates IIaccording to either of the following reaction heat above melting Ringclosure II BrCH COOR IX I (heat with or without inert solvent) ReactionA comprises heating an admixture of equimolar amounts of Compounds IIIand IV at temperatures up to from 150 to 200 C. (preferably in vacuo) orby refluxing the admixture in an inert organic solvent, such as dioxane,toluene or xylene, to obtain Compound VI. Reaction B starts rapidly atroom temperature (20 C.) on admixture of Compounds III and V in an inertsolvent, such as tetrahydrofurane, dioxane, dimethylformamide anddimethylsulfoxide, with evolution of carbon dioxide; completion of thefirst step is effected by heating for fifteen minutes on a water bath;Compound VI is thereafter precipitated in essentially quantitative yieldon addition of water to the obtained solution.

The first step of reaction C is conducted in aqueous alkali, eg. sodiumhydroxide, (Schotten-Ba-umann conditions), preferably in admixture witha water-miscible solvent, e.g. tetrahydrofurane and dioxane.

To protect the amino group of intermediate VI during theBischler-Napieralski ring closure, the use of said intermediate in theform of its tosylate is satisfactory, but other protecting groups, suchas acetyl, benzoyl and mesyl, are alternatively employed. Thepreparation of the tosylate is carried out in the usual Well-knownmanner either under Schotten-Baumann conditions or in pyridine.

Ring-closure of the tosylate to the corresponding 3,4-dihydroisoquinoline compound (Bischler-Napieralski reaction) occurs onboiling in xylene with phosphorus pentoxide or refluxing in phosphorusoxychloride. Other known dehydrating agents and reaction conditions alsobring about this reaction.

The protecting tosyl group is split off in essentially quantitativeyield on standing for from 2 to 15 hours in concentrated sulfuric acidat room temperature.

Catalytic hydrogenation of the 3,4-dihydroisoquinolines in acetic acid(platinum catalyst) yields the 1,2,3,4- tetrahydroisoquinolines II.Either palladium or nickel hydrogenation catalysts are alternativelyemployed. Other reducing agents for 3,4-dihydroisoquinolines are, e.g.,zinc/hydrochloric acid, tin/hydrochloric acid and iron/ hydrochloricacid.

Compound IX is prepared by refluxing Compound II and bromoacetic esterin alcoholic solution in the presence of, i.e. with, a tertiary base,e.g. triethylamine, for from one to two hours. Saponification of theester group of IX to the amino acid X is conducted in aqueous alcoholicalkali, and the amino acid is precipitated by adding to the saponifiedproduct an equivalent of acid, e.g. hydrochloric acid.

Amino esters IX are alternatively directly cyclized to tetracyclics Ieither by heating to a temperature of from 150 to 200 C. or by refluxingfor several hours, e.g. two to ten hours, in an inert organic solvent,such as dioxane, toluene and xylene. Amino acids X cyclize readily uponheating same above their melting points for from ten to sixty minutes. i

When R of Compound I is a hydrogen atom, it is readily replaced :by alower alkyl, a lower al-kenyl or a lower alkinyl group according to thereaction R is either lower alkyl, e.g. methyl, ethyl, isopropyl andbutyl; lower alkenyl, ezg. allyl; or lower alkinyl, e.g. propargyl; and

Y is halo, e.g. bromo (Br) and iodo (I).

Reaction F is conducted under the usual conditions for reacting an amidonitrogen-bound hydrogen atom with a halide, i.e. the amide and a stronganhydrous base, e.g. potassium tertiary butoxide and sodium ethoxide, inan inert organic solvent, such as dioxane, dimethylformamide anddimethylsulfoxide, are admixed with an equivalent of halide, R'Y, e.g.methyl iodide.

Compounds I have one asymmetric center when both R and R are the sameand two asymmetric centers when R and R are dilferent. In the formercase Compounds I, therefore, exist as a racemate or two opticalantipodes; whereas there are four optically active stereoisomers in thelatter case. All of the steriosomers and the racemic mixtures (orracemates) are within the scope of this invention. Resolution of racemicmixtures int-o optical antipodes or disastereoisomeric compounds iselfected according to procedures well-known tothe art-skilled.

Exemplary embodiments are presented in the following table. The startingmaterials and the intermediates (see reactions A to F) are reflected bythe definition of substituents.

Stereo isomeric form Whereln: Me stands for methyl; Et stands for ethyl;Pr stands for propyl; Bu stands for hutyl; Al stands for allyl and P1stands [or p p rsy Where the stereoisorneric form is undefined, either araeemate, a racemic mixture or a partial racemate is indicated,

Also within the scope of the instant invention are pharmaceuticallyacceptable acid addition salts, e.g. hydrochloride, furmarate, formate,acetate, citrate, sulfonate, maleinate, tartrate, methane sulfonate,salicylate and hydrosulfate, of Compounds I. These acid addition saltsare prepared from the corresponding free bases according to procedureswell-known to the art-skilled.

Compounds I and their pharmaceutically acceptable acid addition saltshave central nervous system (CNS) activity. Racemates, racemic mixturesand optically a tive isomers have anticonvulsant activity, barbituratepotentiation and reinduction, and amphetamine antagonism activity. Theyare useful as anticonvulsants, sedative and/ or sedative-hypnotics,tranquilizers, antianxiety agents, antidepressants and analgesics. The(+)-stereoisomers of Compounds I with one asymmetric center arematerially more active in anticonvulsant and barbiturate potentiationactivity than their (-)-counterparts.

Said compounds are administered either orally or parenterally from twoto three times per day (for higher mammals) in average daily doses offrom one to two milligrams per kilogram mg./kg.) of body weight. Theyare used in the same manner at the same approximate dosage and for thesame purpose as oxazepam.

N -oxides of Compounds I are prepared by the oxidation of thecorresponding Compound I with peracid, e.g. perbenzoic acid,m-chloroperbenzoic acid and peracetic acid, or with hydrogen peroxide ina suitable solvent, such as ethanol, acetic acid and acetic anhydride.

The N -oxides of Compounds I (including racemates, racemic mixtures andoptically active isomers) also have CNS activity, e.g. anticonvulsantand muscle relaxant, and are useful as such in the same manner asCompounds I, but with doses containing from three to four times theamount of active ingredient.

Each of the pharmaceutically active compounds of this invention may be,e.g., incorporated, for oral administration, in a tablet as the soleactive ingredient. A typical tablet is constituted by from 1 to 2percent binder, e.g. tragacanth; from 3 to percent disintegrating agent,e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage ofactive ingredient; and q.s. 100 percent of filler, e.g. lactose; allpercentages being by weight. Tablets are prepared according to standardtabletting techniques, which are well-known in the art, em-

ploying the necessary amounts of conventional granu-v lating liquids,e.g. alcohol SD-30 and purified water. An exemplary tablettingformulation for the instant active compound is Alcohol SD-30, purifiedwater, q.s.

The following examples illustrate the invention, all temperatures beingin degree centigra de, parts and percentages being by weight unlessotherwise specified, and the relationship between parts by weight andparts by volume being the same as that between the kilogram and theliter.

Example l-N- B-phenethyl -2-nitrobenz amide To 3 parts ofB-phenethylamine and 1.1 parts of sodium hydroxide (in 7 parts by volumeof water) add dropwise (with vigorous stirring) 5 parts ofo-nitro-benzoyl chloride within a period of 30 minutes and at atemperature of from 35 to 40. Continue stirring for an additional thirtyminutes.

Filter off the crystalline reaction product (title compound), andrecrystallize same from benzene to obtain white prisms, melting point(M.P.) 117. [See Rodionov, V. M., and Yarvorskaya, E. V., J. Gen. Chem.(USSR), 13, 491, 1943; and C. A., 38, 3285 Replacing the phenethylamineby an equivalent of homopiperonylamine results in the preparation of thecorresponding Compound VIII. Replacing the o-nitrobenzoyl chloride by anequivalent of S-bromo-Z-nitrobenzoyl chloride results in the preparationof N-(fl-phenethyl -5-bromo-2-nitrobenzamide.

Example 2.1-(2-nitro-phenyl)-3,4-dihydroisoquinoline Add 12 parts ofphosphorus pentoxide (P 0 to a solution of 5 parts ofN-(fl-phenethyl)-2-nitrobenzamide in25 parts by volume of xylene andreflux the resulting reaction mixture for two hours.

Thereafter evaporate the organic solvent in vacuo, and then decomposethe sticky residue with ice water. Extract the obtained water layer withdiethylether to remove residual starting material. Then make theextracted water layer alkaline with concentrated sodium hydroxide.

Filter off the resulting crystalline title compound, and recrystallizesame from diethylether/pentane to obtain yellow prisms, M.P. 86 to 87.[See C.A., 38, 3285 supra] Replacing theN-(fl-tphenethyl)-2-nitrobenzamide by an equivalent of eitherN-(homopiperonyl)-2-nitrobenzamide orN-(3-chlor0-B-phenethyl)-5-chloro-2-nitrobenzamide results in thepreparation of the corresponding dihydroisoquinolines.

Example 3.-l-(2-aminophenyl)-1,2,3,4- tetrahydroisoquinoline NHa andcrystallize the residue from ethanol/water to obtain the title compoundas white prisms, M.P. 107.

Replacing the 1- (2-nitrophenyl)-3,4-dihydroisoquinoline by anequivalent of either l-(2-nitrophenyl)-6,7- methylenedioxy3,4-dihydroisoquinoline or 1-(5-bromo-Z-nitrophenyl)-7-bromo-3,4-dihydroisoquinoline results in thepreparation of the corresponding tetrahydroisoquinolines II.

Example 4.--1-(Z-aminophenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisoquinoline Reflux for 2.5 hours a mixture of 2 partsof 1-(2-aminophenyl)-l,2,3,4-tetrahydroisoquinoline, 3 parts of ethylbromoacetate and 1 part of triethylamine in 10 parts by volume ofethanol. Evaporate the resulting solution to dryness; dissolve theresidue in 20 parts by volume of ethanol and 10 parts by volume of 2 Nsodium hydroxide; and heat the obtained solution one hour at 60.

Add to the thus-heated product 10 parts by volume of 2 N hydrochloricacid. Then evaporate the ethanol in vacuo to crystallize out the titlecompound.

Replacing the 1-(2-aminophenyl) l,2,3,4 tetrahydroisoquinoline by anequivalent of either 1- (2-arninophenyl)6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline or 1-(2-amino 5chlorophenyl) 7 ethoxy-1,2,3,4- tetrahydroisoquinoline results in thepreparation of the corresponding 2 carboxymethyl 1,2,3,4tetrahydroisoquinolines X.

Example 5.5,9,10,l4b-tetrahydroisoquino[2,1-d] [1,4] benzodiazepin-6(7H) -one Heat crude 1 (2 aminophenyl) 2carboxymethyll,2,3,4-tetrahydroisoquinoline at 160 for 30 minutes.Recrystallize the crystalline residue from ethanol to obtain thetetracyclic title Compound I.

Replacing the 1 (2-aminophenyl) 2 carboxymethyl-1,2,3,4-tetrahydroisoquinoline by an equivalent of 1-(2- aminophenyl) 2carboxymethyl 6,7 methylenedioxy- 1,2,3,4-tetrahydroisoquinoline resultsin the preparation of the corresponding Compound I.

Examples 1 to 5 illustrate the individual steps in a synthesis ofCompounds I. Corresponding Compounds I are prepared starting with anyphenethylamine R NH:

and any o-nitrobenzoyl chloride XlI 8 Example6.-N-(fi-phenethyl)-2-nitro-5-chlorobenzamide Add a solution of 6 partsof 2-nitro-5-chloro-benzoylchloride in 6 parts of dioxane at 35 to 40dropwise under vigorous stirring and within 30 minutes to the mixture of3 parts of fl-phenethylamine and 1 part of sodium hydroxide in 15 partsof water and 5 parts of dioxane. Stir another 30 minutes. Add more waterto crystallize out the product. Recrystallize from ethylacetate/diethylether to obtainN-(fi-phenethyl)-2-nitro-5-chloro-bcnzamide as white prisms, M.P. 102 to104.

Example 7.1-(2-nitro-5-chlorophenyl)-3,4- dihydroisoquinoline Add 2parts of phosphorus pentoxide to a hot solution of 1 part ofN-(fi-phenethyl)2-nitro-5-chlor0-benzamide in 5 parts of xylene andreflux the mixture for 5 hours.

Thereafter evaporate the organic solvent in vacuo and then decompose thesticky residue with ice water. Extract the obtained water layer withdiethylether to remove residual starting material. Then make theextracted water layer alkaline with concentrated sodium hydroxide.

Filter ofi? the resulting crystalline title compound and recrystallizesame from diethylether/pentane to obtain yellow prisms, M.P. 124 to 125.

Example 8.--1-(Z-amino-S-chloro-phenyl)-l,2,3,4- tetrahydroisoquinolineCatalytically hydrogenate (0.2 part of platinum catalyst) a solution of1 part of 1-(2-nitro-5-chlorophenyl)- 3,4-dihydroisoquinoline in 5 partsof acetic acid at room temperature and atmospheric pressure. Afterfiltration and evaporation in vacuo crystallize the residue fromethylacetate/diethylether to obtain1-(2-arnino-5-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline as whitecrystals, M.P. 125 to 127.

Example 9.1- 2-amino-5-chlorophenyl)-2-carboxymethyl-1,2,3,4-tetra'hydroisoquinoline Reflux the mixture ofparts of 1-(2-amino-5-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline, 4parts of ethyl bromoacetate, 2.5 parts of triethylamine and 1 part ofsodium iodide in 100 parts by volume of ethanol for two hours. Evaporatethe reaction mixture to dryness, dissolve the residue in 150 parts byvolume of ethanol and 40 parts by volume of 2 N sodium hydhroxide. Heatthe obtained solution 3 hours at 60. Evaporate the alcohol in vacuo fromthe resultant, whereupon some starting material precipitates out.Thereafter add to the supernatant 40 parts by volume of 2 N hydrochloricacid to precipitate out the reaction product as fine white crystals.Recrystallize same from ethanol to obtain 1-(2- amino 5chlorophenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisoquinoline, M.P. 163to 165.

Example 10.-2-chloro-5,9, 10, 14b-tetrahydroisoquino [2,1-d][1,4]ibenzodiazepin-SUH)-one Heat crude 1(Z-amino-S-chlorophenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisquinolineat 170 for 30 minutes. Recrystallize the crystalline raw-product fromethanol to obtain 2-chloro-5,9,10,14b-tetrahydroisoquino- [2,1-d][1,4]benzodiazepin 6(7H) one as white prisms, M.P. 220 to 222".

Example 1 l.-2chloro-5-ethyl-5,9,10,14b-tetrahydroisoquino[2,1-d] [1,4]benzodiazepin 6 (7'H -one Add 0.8 part of potassium tertiary butoxide tothe solution of 2 parts of 2-chloro-5,9,10,14d-tetrahydroisoquiuo[2,1-d] [1,4]benzodiazepin-6(7'H)-one in 25 parts by volume ofdimethylsul'foxide (DMSO) After maintaining the product for fifteenminutes at room temperature, add dropwise thereto 1 part of ethyliodide. Maintain the resultant reaction mixture at room temperature overnight and then dilute same slowly with water, whereby 2-chlo-ro- 5ethyl-5,9,10,14b-tetrahydroisoquino[2,1d] [1,4]benzodiazepin-6(7H)-oneprecipitates out as white needles, M.P. 171 to 173.

This example illustrates reaction F. In the same manner a nitrogen-boundhydrogen atom in the 5-position of any compound I is replaced by anyother substituent R Replacing the 2 chloro 5,10,14btetrahydroisoquino[2,1-d][1,4]benzodiazep-in-6(7H)-one by an equivalentof2-chloro12,13-methylenedioxy-5,9,10,14b-tetrahydroisoquino[2,1-d][1,4]benzodiazepin-6(7H)one results in the preparation of the corresponding compound I.

Replacing the ethyl iodide by an equivalent of either propargyl bromideor allyl chloride results in the preparation of a compound I having thecorresponding substituent R NHCH3 Heat the mixture of 2 parts of5-chloro-N-methyl-isatoic anhydride and 3 parts of fl-phenethylamine in10 parts of dioxane for 15 minutes on a Water bath, whereby vigorouscarbon dioxide evolution takes place. Add water to the obtained solutionto precipitate N-(B-phenethyD-Z-methylamino-5-chloro-benzamide, M.P. 129to 131.

This example illustrates reaction B. Replacing the ,B-phenethylaminewith an equivalent of any compound III, e.g., 4-chloro-B-phenethylamine,results in the preparation of the corresponding compound VI. Likewise,replacing the 5-chloro-N-methyl-isatoic anhydride by an equivalent ofeither S-chloro-isatoic anhydride or isatoic anhydride results in thepreparation of the corresponding compound VI.

Example 13.Tosylate of N-(B-phenethyD-Z-methylamino-5-chloro-benzamideAdd 1 part of p-toluene sulfonyl chloride to the solution of 1 part ofN-(jB-phenethyl)-2-methylamino-5-chlorobenzamide in 5 parts of pyridineand heat the obtained mixture at 60 for 1.5 hours. Evaporate theresultant in vacuo, add 3 parts of acetone and 1 part of water to theproduct, and shake the obtained reaction mixture for 30 minutes. Afterevaporation of the acetone, add ethyl acetate thereto and extract theorganic layer thoroughly with dilute hydrochloric acid and sodiumbicarbonate solution. Dry the organic phase over sodium sulfate andevaporate the dried product to dryness to obtain the tosylate ofN-(fi-phenethyl)-Z-methylamino-5-chl0ro-benzamide as an oily residue.

Replacing the N (B phenethyl) 2 methylarnino-S- chloro-benzamide byanequivalent of eitherN-(homopiperonyl)-2-methylamino-5-chloro-benzamide or N-(B-phenethyl)-2-amino-5-chloro-benzamide results in the preparation of thecorresponding tosylate.

Example 14.1-(Z-methyltosylamino-S-chloro-phenyl)-3,4-dihydroisoquinoline hydrochloride CH3 .HCl

with concentrated aqueous sodium hydroxide solution, and extract thealkaline product with methylene chloride. After drying and evaporatingthe organic solvent, dissolve the oily residue in diethylether, andprecipitate the hydrochloride of1-(Z-methyltosylamino-S-chloro-phenyl)-3,4- dmydroisoquinoline, M.P. 240to 241, by bubbling hydrogen chloride gas through the obtained ethersolution.

Example l5.l- 2-methylamino-5-ch1oro-phenyl 3,4-dihydroisoquinolineGradually add 4 parts by volume of concentrated sulfuric acid undercooling to 1 part of the hydrochloride described in Example 14 andmaintain the obtained solution at room temperature overnight. Pour saidsolution on ice; make it alkaline with sodium hydroxide; and extract thealkaline solution with methylene chloride. Dry and evaporate the organicsolvent to obtain 1-(2-methylamino-S-chloro-phenyl)-3,4-dihydroisoquinoline as an oily residue.

Example 16.1-(Z-methylamino-S-chloro-phenyl)- 1,2,3,4-tetrahydroisoquinoline Catalytically hydrogenate (0.02 part ofplatinum catalyst) a solution of 1 part of crude 1-(2-methylamino-5-chloro-phenyl)-3,4-dihydroisoquinoline (described in Example 15) in 8parts of acetic acid at room temperature and under atmospheric pressure.Filter off the catalyst, evaporate the filtrate in vacuo, dissolve theresidue in methylene chloride, and shake the resulting solution withdilute sodium hydroxide (aq.) solution. After drying and concentratingthe organic layer, add pentane thereto to crystallize 1 (2methylamino-S-chloro-phenyl)-1,2,3,4- tetrahydroisoquinoline as Whiteprisms, M.P. 141 to 143 Example 17.-l-(Z-methylamino--chloro-phenyl)-2-carboxymethyl-l,2,3,4-tetrahydroisoquinoline 12 Example18.2-chloro-5-methyl-5,9,10,14b-tetrahydroisoquino 2, l-d] [1,4]benzodiazepin-6 (7H -one CH Cl Heat crude 1-(Z-methylamino-5-chlorophenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisoquin0line (from Example 17)to 140 for 1 hour. Dissolve the raw product in diethylether, andprecipitate the hydrochloride, M.P. 267 to 270, of 2 chloro5-methyl5,9,l0,l4b-tetrahydroisoquino[2,1-d][1,4]benzodiazepin-6(7H)-onefrom the resulting solution by bubbling therethrough dry hydrogenchloride gas. Precipitate the free base from the aqueous solution of thehydrochloride by adding thereto sodium hydroxide; recrystallize the freebase, M.P'. to 97, from ethanol-water.

Examples 12 to 18 illustrate reactions B and B. These reactions areeffected in the same manner to prepare corresponding compounds I whereinR and R together, form methylenedioxy and to prepare correspondingcompounds I wherein R is a hydrogen atom.

Example 19 .N-( homoveratryl -2-methylamino-5- chloro-benzamide ornoq CHO- IIIH Heat the mixture of 1 part of S-chloro-N-methyl-isatoicanhydride and 1 part of homoveratrylamine in 4 parts of dioxane forfifteen minutes on a water bath, whereby vigorous carbon dioxideevolution takes place. Add water to the resulting solution toprecipitate N-(homoveratryl)-2- methylamino-S-chloro-benzamide, M.P. 96to 98.

Example 20.-Tosylate of N-(homoveratryl)-2-methylamino-S-chloro-benzamide Example21.-1-(2-methyltosylamino-5-chloro-phenyl)6,7-dimethoxy-3,4-dihydroisoquinoline CHQO Dissolve the crude tosylate(from Example 20) in parts of hot xylene, and add 2 parts of phosphoruspentoxide to the obtained reaction mixture. Reflux said reaction mixturefor hours. Evaporate the xylene in vacuo and decompose the stickyresidue by addition thereto of ice. Make the aqueous mixture alkalinewith concentrated aqueous sodium hydroxide solution, and extract Withethyl acetate. Extract the combined organic layers with dilutehydrochloric acid. Make the Water layers alkaline again in the samemanner as above-described, and extract same with methylene-chloride toobtain 1-(2-methyltosylamino- S-chloro-phenyl)-6,7edimethoxy-3,4dihydroisoquinoline as an amorphous residue.

Example 22.1-(Z-methylamino-5-chloro-pheny1)-6,7-dimethoxy-3,4-dihydroisoquinoline NIL-CH3 Maintain the solution of 1part of the crude product (described in Example 21) in 2.5 parts ofconcentrated sulfuric acid at room temperature over night. Thereafteradd thereto ice water and sodium hydroxide and extract the thus-obtainedsmeary precipitate with methylenechloride. Evaporate the solvent andcrystallize the residue from ethanol to obtain1-(Z-methylamino-S-chlorophenyl)-6,7-dimethoxy 3,4 dihydroisoquinoline,M.P. 110 to 112".

Example 23 .-1-(Z-methylamino-5-chloro-phenyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline C1130 NH NH-CH;

14 Example 24.-1-(Z-methylamino-5-chloro-phenyl)-2-carboxymethyl 6,7dimethoxy 1,2,3,4 tetrahydroisoquinoline CHaO NCH2C O OH CHSO NH-CH:

at 60. Evaporate the alcohol in vacuo, whereby a small amount ofstarting material crystallizes out. Filter same oif. Add 3 parts of 2 Nhydrochloric acid to the filtrate to precipitate1-(2-methylamino-5-chloro-pheny1)-2-carboxymethyl-6,7-dimethoxy 1,2,3,4tetrahydroisoquinoline.

Example 25 .-2 chloro 12,13 dimethoxy 5 methyl- 5,9,10,l 4btetrahydroisoquino[2,l-d] [1,4] benzodiazepin-6(7H)-one Heat crudel-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-6,7-dimethoxy 1,2,3,4tetrahydroisoquinoline (from Example 24) at for 1 hour. Crystallize theraw product from ethylacetate to obtain the title compound, M.P. to 177.

Examples 19 to 25 illustrate the preparation of compounds I havingsubstituents in the 12- and Iii-positions. In the same manner thecorresponding 12,13-methylenedioxy-compounds I are prepared fromcorresponding starting materials and intermediates. Repeating theprocedures of Examples 19 to 25 replacing the homoveratrylamine startingmaterial (see Example 19) by an equivalent of either fi-methyl or19,;3-dimethyl-homoveratrylamine results in the preparation of thecorresponding compounds I.

Example 26.-Resolution of racemic l-(2-methylamino-S-chloro-phenyl)-1,2,3,4-tetrahydroisoquinoline into its opticalantipodes NH-CH racemate 100 parts of methylene chloride. Onconcentrating this mixture, only the tartrate of the base crystallizes.

Filter oil the precipitate and free the base from this salt bydistributing the filtrate between methylene chloride and dilute aqueoussodium hydroxide solution; dry the organic phase and evaporate thesolvent in vacuo. Crystallize the residual crude base from ethanol toobtain 1 (Z-methylamino-S-chloro-phenyl)-1,2,3,4-tetrahydroisoquinoline,

Evaporate the filtrate of the tartrate of the (+)-base to dryness invacuo and distribute the residue between methylene chloride and diluteaqueous sodium hydroxide solution. Dry the organic phase and evaporatethe solvent therefrom in vacuo. Transfer the residue, consistingessentially of the base, in exactly the same way as described above tothe crystalline L()-tartrate by addition of L()-tartaric acid. The freebase ()-1-(2-methylamino-S-chloro-phenyl) 1,2,3,4tetrahydroisoquinoline, prepared from the tartrate as described for thebase, has

[ ii-3G 27-8 (0.=2 in ethanol) Example 27-1-(Z-methylamino-S-chloro-phenyl)-Z-carboxymethyl-1,2,3,4-tetrahydroisoquinoline Reflux the mixture of 8parts of )-1-(2-methylamino-S-chlorophenyl)-1,2,3,4-tetrahydrisoquinoline, parts of ethylbromoacetate and 6.5 parts of triethylarnine in 75 parts by volume ofethanol for two hours. Evaporate the obtained solution to dryness;dissolve the residue in 80 parts by volume of ethanol and 32 parts byvolume of 2 N sodium hydroxide, and heat this solution one hour to 60.Evaporate the alcohol in vacuo, whereby a small amount of startingmaterial crystallizes out and is filtered off. On addition of 32 partsby volume of 2 N hydrochloric acid,(+)-1-(Z-methylamino-5-chloro-phenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisoquinoline precipitates out,

M22 +64.5 (0. 1.3 in ethanol) Example 28.-()-2-chloro-5-methyl-5,9,10,14b-tetrahydroisoquino[2,1-d] [1,4]benzodiazepin-6 (7H) -one hydrochloride Heat crude-1-(2-methylamino-S-chloro-phenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisoquinoline to 140 for one hour.Dissolve the raw product in acetone and precipitate the hydrochloride of()-Z-chlorD-S-methyl- 5,9,10,14b tetrahydroisoquino[2,1-d][1,41benz0diazepin- 6(7H)-one by bubbling in dry hydrogen chloride gas,[a] =-313 (C.=2 in water). Precipitate the free base from the aqueoussolution of the hydrochloride on addition of sodium hydroxide andrecrystallize from ethanol-water, M.P. 156 to 157,

[021E3 L09 (o.=0.6 in ethanol) 5 Example 29.(-1-(Z-methylamino-S-chloro-phenyl 2-carboxymethyl-1,2,3 ,4-tetrahydroisoquinoline 64 (0. 1.5 in ethanol) Example 30.--(+)-2-chloro-5-methyl-5,9,10,14b-tetrahydroisoquino[2,l-d][1,4]benzodiazenpin-6(7H)-one bydrochloride C 0 .HCl

CH3 C1- Heat crude )-l-(Zamethylamino-S-chloro-phenyl)-2-carboxymethyl-1,2,3,4-tetrahydroisoquinoline (from Example 29) at 140for one hour. Dissolve the raw product in acetone and precipitate thehydrochloride of )-2- chloro-5-methyl-5,9,10,l4b-tetrahydroisoquino[2,1d] [1, 4] benzodiazeopin-6(7H)-one,

+310 (c.=2 in Water) by bubbling in dry hydrogen chloride gas.

Precipitate the free base from the aqueous solution of the hydrochlorideby addition of sodium hydroxide and recrystallize it from ethanol-water,M.P. 156 to 157,

[ 136 +4100 -=O.7 in ethanol) An alternative method of preparingcompounds I from available compounds is in accord with the followingreactions:

b l e For reaction G a solution of the acid chloride XIII in an inertsolvent is added dropwise into a solution of phenethylamine III in aninert solvent and pyridine (as a base). The inert solvent for each ofIII and XIII is, indpendently, e.g., dioxane and tetrahydrofurane(TI-IF). Alternatively, Schotten-Baumann conditions are employed tocarry out this .acylation for the preparation of compounds XIV.

Compound XVI is either ammonia (NH or lower alklamine. The first step ofreaction H is a standard amination wherein a ring halogen atom isreplaced, and the second step is a reduction of adouble bond with sodiumborohydride to prepared compounds XVIII. It is apparent that each of thecompounds XVII and XVIII contains a secondary amino group when compoundXVI is a lower alkyl- H amine, such as methylamine and ethylamine.

In the first step of reaction I compound XVIII is reacted with a loweralkyhaloacetate, e.g. ethylbromoacetate (Z is either chloro or bro-mo,and R is lower alkyl, preferably methyl or ethyl). The resulting esterXIX is saponified with sodium hydroxide to produce the acid XX. Ringclosure (to obtain compound I) is elfected by heating compound XX overits melting point for from one to three hours.

Example 3 1.--N- B-phenet-hyl -2chloro-5-nitrobenzarnide Add dropwise(within a period of thirty minutes) a solution of 33 parts of2-chloro-5-nitrobenzoyl chloride in 70 parts by volume of dry dioxane toa mixture (under agitation) of 20 parts of phenethylamine, 20 parts byvolume of pyridine and 50 parts by volume of dioxane. Continue stirringthe resultant at room temperature (20) for two hours before addingthereto 20 parts of ice. To the thus-cooled material (being stirred) adddropwise dilute sodium hydroxide until the pH is 1'0. Dilute thethus-obtained mixture with 200 parts by volume of water to precipitatethe title compounds, melting point (M.P.) 155. Filter the precipitateand dry same in vacuo.

Example 32.-1-(2-chloro-5-nitrophenyl)-3,4-dihydroiso quinoline OaN .fate and then evaporate the solution to dryness in vacuo.

Crystallize the thus-obtained residue from diethylether to obtain thetitle compound,

a OaN Heat (autoclave) for 12 hours at 55 to 60 in. 10 parts by volumeof liquid methylamine a mixture of 1 part of 1(2-chloro-5-nitrophenyl)-3,4-dihydroisoquinoline, 0.05 part of cuprouschloride and 0.05 part of copper powder. Cool the resultant andevaporate the methylamine therefrom at room temperature. Admix thethus-obtained residue with 10 parts by volume of methylene chloride andfilter off insoluble material. Wash the filtrate twice with water; drythe washed filtrate over sodium sulfate and evaporate in vacuo to obtain0.9 part of the title compound as an amorphous residue. Crystallize saidtitle compound from diethylether to obtain light yellow prisms, MP. 148.

Replacing the methylamine with an equivalent of either ethylamine orpropylamine results in the preparation, in similar manner, of thecorresponding compound XVII.

1 9 Example 34.1-(2-methylamino-5 nitrophenyl) -l,2,3,4-tetrahydroisoquinoline Reflux for two hours in 30 parts by volume of 95%ethanol and 6 parts by volume of chloroform, a mixture of 1 part of1-(Z-methyl-amino-S-nitrophenyl)-3,4dihydroisoquinoline and 0.6 part ofsodium borohydride. Cool the obtained solution before admixing same with2 N hydrochloric acid to destroy excess sodium borohydride. Alkalize theresultant with 2 N sodium hydroxide solution and distill off most of theethanol in vacuo. Extract the resultant mixture three times with ethylacetate, dry the organic phase (ethyl acetate solution) over sodiumsulfate and then evaporate same in vacuo to obtain 1 part of crudecrystalline title compound, M.P. 178, recrystallized from diethylether.

Replacing the title compound of Example 33 with an equivalent of either1-(2-ethylamino-S-nitrophenyl)-3,4- dihydroisoquinoline or1-(2-propylamino-5-nitrophenyl)- 3,4-dihydroisoquinoline results in thepreparation, in similar manner, of the corresponding compound XVIII.

Example 35 1- (2-methylamino-5 -nitrophenyl -2- carboxymethyl-1,2,3,4-tetrahydroisoquinoline Reflux for four hours in 300 parts by volumeof ethanol and 100 parts by volume of dioxane, a mixture of 30 parts of1- (2-methylamino-S-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline, 37parts of ethyl bromoacetate, 21 parts by volume of triethylamine and 16parts of sodium iodide. Evaporate the solvent in vacuo; dissolve theresidue in ethylacetate and wash the ethylacetate solution with waterand dilute sodium hydrogen carbonate (NaHCO solution. Dry the organicphase over sodium sulfate and then evaporate same in vacuo. Dissolve theobtained residue in 50 parts by volume of ethanol and 13 parts by volumeof dioxane; add 17 parts by volume of 2 N sodium hydroxide to thethus-produced solution and heat the resulting mixture for 4 hours at 60.Neutralize the resultant solution with 17 parts by volume of 2 Nhydrochloric acid, and dilute with 100 parts of Water to precipitate thetitle compound, M.P. 155.

Replacing the ethyl bromoacetate with an equivalent of either ethylchloroacetate or methyl bromoacetate results in the preparation, insimilar manner, of the corresponding compound XIX as an intermediate forthe identical title compound.

Replacing the title compound of Example 34 with an equivalent of either1-(Z-ethylamino-5-nitrophenyl)-1,2, 3,4-tetrahydroisoquinoline or1-(2-propylamino-5-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline resultsin the preparation, in similar manner, of the Corresponding compound XX.

20 Example 3 6.2-nitro-5 -methyl-5 ,9 10, 14b -tetrahydroisoquino[2,1-d][1,4] benzodiazepin-6 (7H) -0ne Heat the title compound of Example 35 atfor 1 /2 hours. Crystallize the obtained amorphous residue fromethylacetate-diethylether to obtain the title compound as yellow prisms,M.P. 223

Replacing the title compound of Example 35 with an equivalent of either1-(Z-ethylamino-S-nitrophenyl)-2- carboxymethyl 1,2,3,4tetrahydroisoquinoline or 1 (2- propyla-rnino-S-nitrophenyl) 2carboxymethyl 1,2,3,4- tetrahydroisoquinoline results in thepreparation, in similar maner, of the corresponding compound I.

Example 3 7.1-(2-amino-5-nitrophenyl)- 3,4-dihydroisoquinoline Heat(autoclave) for 12 hours at 55 to 60 in 20 parts by volume of liquidammonia, a mixture of 1 part of the title compound of Example 32, 0.05part of cuprous chloride and 0.05 part of copper powder. Cool theresultant and evaporate the ammonia at room temperature. Admix thethus-obtained residue with 10 parts by volume of methylene chloride andfilter ofi insoluble material. Wash the organic (methylene chloride)phase twice with water; dry over sodium sulfate and evaporate in vacuoto obtain 0.9 part of the crude title compound, which is crystallizedfrom diethylether as yellow prisms, M.P. 152.

Example 38.1-(2-amino-5-nitrophenyl)- 1,2,3,4-tetrahydr0isoquinolineReflux for two hours in 30 parts by volume of 95 ethanol and 6 parts byvolume of chloroform, a mixture of 1 part of the title compound ofExample 37 and 0.6 part of sodium borohydride. Cool the obtainedsolution before admixing same with 2 N hydrochloric acid to destroyexcess sodium borohydride. Alakize the resultant with 2 N sodiumhydroxide solution and distill off most of the ethanol in vacuo. Extractthe resultant mixture three times with ethylacetate, dry the organicphase (ethylacetate solution) over sodium sulfate and then evaporatesame in vacuo to obtain 1 part of crude crystalline title compound, M.P.recrystallized from ethylacetate.

23 Example44.2-chloro-5,10-dimethyl-5,9',10,14b-tetrahydroisoquino[2,1-d] [1,4]benzodiazepin-6 (7H) -one (a) N-(Z-phenylpropyl)-2-methylamino 5chlorobenzamide.

NH-CH;

Heat the mixture of 2 parts of 5-chloro-N-methylisatoic anhydride and1.6 parts of Lphenylpropylamine in 10 parts by volume of dioxane for 15minutes on a water bath, whereby vigorous carbon dioxide evolution takesplace. Add water to the obtained solution to precipitate 3 parts of (a),M.P. 100 to 103.

(b) Tosylate of (a) IIIH i CH SW CH.

Add 1 part of p-toluenesulfonyl chloride to the solution of 0.8 part of(a) in 2.5 parts by volume of pyridine, and heat the obtained mixture at60 for 1.5 hours. Evaporate the resultant in vacuo, add 3 parts byvolume of acetone and 1 part by volume of water to the product, andshake the obtained reaction mixture for 30 minutes. After evaporation ofthe acetone, add ethyl acetate to the remainder and extract the organiclayer thoroughly with dilute hydrochloric acid and sodium bicarbonatesolution. Dry the organic phase over sodium sulfate and evaporate thethus-dried organic phase to dryness to obtain 1 part of (b), M.P. 89 to91 with decomposition.

(c) I-(Z-methyltosylamino chlorophenyl)-4-methyl-3,4-dihydroisoquinoline hydrochloride \m-Q-orn Add parts of the tosylate(b) to 43 parts by volume of phosphorus oxychloride and reflux theresulting mix ture for hours. Cool the refluxed product to roomtemperature and evaporate in vacuo. Dissolve the obtained residue in 300parts by volume of methylene chloride. Wash the thus-prepared solutionfirst with ice-cold 1 N (aq.) sodium hydroxide (2 washings withapproximately 120 parts by volume of the sodium hydroxide solution foreach), then with water and finally with saturated (aq.) sodium chloridesolution.

Dry the thus-Washed organic phase over sodium sulfate and evaporate theobtained solution in vacuo. Dissolve the residue in 60 parts by volumeof acetone, and saturate the resulting solution with dry hydrogenchloride gas. Add 30 parts by volume of diethylether to the saturatedsolution to precipitate 5.2 parts of (c), M.P. 254.

124 (d) 1-(2-methylamino 5 chlorophenyl)-4-rnethy1-3,4-

dihydroisoquinoline I CH3 NlI-Clla (e) 1-(2 methylamino 5 chlorophenyl)4 methyl- 1,2,3,4-tetrahydroisoquinoline cis" (as racemic mixture) trans(as racemic mixture) Suspend 18.5 parts of (d) in 200 parts by volume ofethanol, add 7 parts of sodium borohydride to the obtained suspension,and reflux the resultant for 1 hour. Cool the refluxed product to roomtemperature, and then acidify with 2 N hydrochloric acid. Thereafter add2 N (aq.) sodium hydroxide until the pH of the obtained solution isabout 9. Evaporate in vacuo to one third of volume. Extract theconcentrated solution twice with water and saturated sodium chloridesolution, dry the thus-washed material over sodium sulfate, andevaporate the dried resultant in vacuo to obtain an oily residue.Crystallize the oily residue from diethylether/pentane to obtain 14parts of (e), cis form, M.P. 142 to 144, and 2.2 parts of (e), transform, M.P. (after recrystallization from diethylether/pentane) 81 to 84.

(f) 1-(2 methylamino 5 chlorophenyl) 2 carbomethoxymethyl-4-methyl-1,2,3,4-tetrahydroisoquinoline Dissolve 2 parts of (e), cis form, in 20 partsby volume of absolute ethanol, and mix the obtained solution with 1.7parts of methyl bromoacetate and 2 parts of triethylamine. Reflux theresulting mixture for four hours. Then evaporate the solvent.

Mix the residue with 200 parts by volume of ethylacetate and parts byvolume of water; separate the phases; extract the aqueous phase twicewith 100 parts by volume (each) of ethylacetate; unify the organicphases and Wash them with water and saturated sodium chloride solution;

21 Example 39.--1- (2-arnino-5-nitrophenyl) -2-carb oxymethyl- 1,2,3,4,-tetrahydroisoquinoline N-CHa-C O O H Reflux for four hours in 300parts by volume of ethanol and 100 parts by volume of dioxane, a mixtureof 30 parts of title compound of Example 38, 37 parts of ethylbromoacetate, 21 parts by volume of triethylamine and 16 parts of sodiumiodide. Evaporate the solvent in vacuo; dissolve the residue inethylacetate and wash the ethylacetate solution with water and dilutesodium hydrogen carbonate (NaHCO solution.

Dry the organic phase over sodium sulfate and then evaporate same invacuo. Dissolve the obtained residue in 50 parts by volume of ethanoland 13 parts by volume of dioxane; add 17 parts of 2 N sodium hydroxideto the thus-produced solution and heat the resulting mixture for 2 hoursat 60. Neutralize the resultant solution with 17 parts of 2 Nhydrochloric acid, and dilute with 100 parts of water to precipitate thetitle compound, M.P. 203 to 204.

Example 40.2-nitro-5,9,10,l4b-tetrahydroisoquino [2,1-d][1,4]benzodiazepin-6 (7H)-one Heat the title compound of Example 39 at205 for /2 hour. Crystallize the obtained amorphous residue fromethylacetate-diethylether to obtain the title compound as yellow prisms,M.P. 160 to 165.

Example 41.(i) 2 chloro methyl5,9,10,14btetrahydroisoquino[2,1-d][1,4]benzodiazepin 6(7H)- one-S-oxideDissolve 10 parts of racemic 2-chloro-5-methyl-5,9,10, 14btetrahyd-roisoquino[2, l-d][1,4]benzodiazepin-6(7H) one in 160 parts byvolume of methylene chloride. To the resulting solution at 5 to 10 addwithin a period of 5 minutes and with stirring a solution of 12.2 partsof mchloro-perbenzoie acid in 160 parts by volume of methylene chloride.Continue stirring for a further 5 to 10 minutes before extracting theobtained mixture with 1 N (aq.)

ammonia. Separate to resulting organic phase, dry same over sodiumsulfate, and evaporate to dryness in vacuo. Crystallize the residue fromethyl acetate to obtain 7.1 parts of title compound, M.P. 168 to 170.

Replacing the racemic2-chloro-5-methyl-5,9,10,14btetrahydr-oisoquino[2,1 d][1,4]benzodiazepin6(7H)- one by an equivalent of either 2-bromo-5-ethyl-IO-methyl- 12,13dimethoxy 5,9,10,14b tetrahyd-roisoquino[2,ld] [1,4]benzodiazepin 6(7H)one or 2 nitro 5 methyl 10 ethyl 13 ethoxy 5,9,10,14btetrahydrosioquino[2,1-d][1,4]benzodiazepin-6(7H)-one results in thepreparation, in similar manner, of the corresponding N -oxide.

Example 42.Racemic 2 chloro 5,9,10,14b tetrahydroisoquino[2,1d][1,4]benzodiazepin 6(7H)- Dissolve 12 parts of racemic2-chloro-5,9,10,14b-tetrahydroisoquino[2,1-d][1,4]benzodiazepin-6(7H)-one in parts by volume of methylenechloride and 15 parts by volume of methanol. Cool the resulting clearsolution to 10, and add thereto (within a period of 5 minutes and underagitation) a solution of 15 parts of m-chloroperbenzoic acid in 190parts by volume of methylene chloride. Continue stirring for 10 moreminutes. Add to the thus-stirred material 500 parts by volume of dilute(aq.) ammonia. Shake the resultant to crystallize out the titlecompound. Filter off the crystals, and recrystallize from ethanol/ waterto obtain 9.6 parts of title compound, M.P. 201.

Replacing the racemic2-chloro-5,9,10,14b-tetrahydroisoquino-[2,1-d][l,4]benzodiazepin-6(7H)-oneby an equivalent of either racemic 2-trifluoromethylS-methyl- 10-propyl12 propoxy-5,9,10,14b-tetrahydroisoquino [2,1d][1,4]benzodiazepin-6(7H)-one or racemic 5- propyl 10'-methyl- 12,13-methylenedioxy-5,9, 10, 14b-tetrahydroisoquino[2,1-d] [1,4]benzodiazepin-6 (7H) -one results in the preparation, in similar manner,of thecorresponding racemic N -oxide.

*In order to prepare N -oxides wherein R is lower alkyl, thecorresponding compound I wherein R is lower alkyl can be employed as aprecursor in the same manner as illustrated in Example 41. A typicalprocedure for preparing compounds I wherein R is lower alkyl isillustrated by Example 11.

Example 43 Mix 10 parts of the title compound of Example 30 (in the formof its free base) thoroughly with 10 parts of Tween 80 and 416 parts ofpropylene glycol. Add to the obtained mixture (with stirring) a solutionconsisting of 15 parts of tartaric acid dissolved in 200 parts by volumeof water for injection. Adjust the resulting solution to pH 3.0 with 0.1N (aq.) sodium hydroxide. Bring the obtained solution to 1000 parts byvolume with Water for injection, stir thoroughly, and filter through amillipore filter. Fill '1 milliliter ampuls with this solution under anatmosphere of carbon dioxide, seal the ampuls, and heat sterilize themat 121 for 15 minutes.

Ampul compositions of the type described in this example areadministered either intramuscularly or intravenously according toestablished procedures.

dry the thus-treated organic :phases over sodium sulfate; and evaporatethe dried organic phases in vacuo.

Crystallize the residue by admixture with 75 parts by volume of a 1:1mixture of benzene and pentane. Filter the precipitated crystals toobtain 1 part of (f), cis form, M.P. 111 to 113.

(g) 1 (2 methylamino chlorophenyl) 2carboxymethyl-4-methyl-1,2,3,4-tetrahydroisoquinoline NH-CIIa Dissolve 2parts of (f), cis form, in parts by volume of ethanol. Mix the obtainedsolution with 10 parts by volume of l N (aq.) sodium hydroxide. Refluxthe resulting mixture for 1 hour. Cool the resultant to roomtemperature. Then admix same with 10 parts by volume of 1 N hydrochloricacid. Filter and dry precipitated crystals to obtain (g), cis form, M.P.260 to 266.

(h) 2 chloro 5,10 dimethyl 5,9,10,14b tetrahydroisoquino [2, l-d] [1,4]benzodiazepin'6 (7H) -one fate; evaporate the solvent to about 30 partsby volume.-

Add to the concentrate 100 parts by volume of diethylether. Filter theformed crystals and wash same with diethylether. There are thus obtained7 parts of the trans form, M.P. 187 to 189, of (h).

In the same manner the corresponding cis form, M.P. 179 to 181, of (h)is obtained from the cis form of (f).

Example 45 .2-chloro-5 ,l0,10-trimethyl-5 ,9, l 0,l4b-tetrahydroisoquino [2,1-d] [1,4] benzodiazepin-6(7H) -one (a) N-(AB-dimethylphenethyl) -5-chloro-2-met-hylaminobenzamide H3O CH3 x GDissolve 46.5 parts of B,fi-dimethylphenethylarnine in 250 parts byvolume of dioxane, and add 63 parts of 6- chloro-N-methyl-isatoicanhydride thereto. Stir the resultant for 25 minutes at roomtemperature. Heat the thusobtained reaction mixture for 30 minutes tocool thereafter and then dilute same with 500 parts by volume of water.Filter off the crystals; then dissolve them in methylene chloride, washthe obtained methylene chloride solution with water; dry the organicphase over sodium sulfate and evaporate the solvent in vacuo.Crystallize the residue with diethylether/pentane to obtaine (a), M.P.126 to 127.

(b) N-([3,;8-dimethylphenethyl)-5-chloro-2 tosylmethyla'mi-nobenzamideDissolve 82.5 parts of (a) in 250 parts by volume of pyridine, and addthereto 99 parts of p-toluenesulfonyl chloride. Warm the obtainedmixture on a waterbath (50 to 60) for 6 hours. Thereafter add water todissolve any pyridine hydrochloride. Concentrate the resulting solutionin vacuo. Partition the residue between ethyl acetate and 2 -Nhydrochloric acid; wash the organic layer with 10% (aq.) sodiumbicarbonate solution and with saturated sodi um chloride solution; dryover sodium sulfate; and evaporate in vacuo. Recrystallize thecrystalline residue with methylene chloride/diethylether to obtain (b),M.P. 128 to 130.

(c) 1- 5-chloro-2-tosylmethylaminophenyl -4,4-dimethyl- 3,4-dihydroisoquinoline Dissolve 99 parts of (b) in 550 parts by volumeof phosphorus oxychloride, and reflux the obtained mixture for 15 hours.Cool; evaporate in vacuo; dissolve the resulting residue in methylenechloride and then extract twice with ice cold 1 N (aq.) sodium hydroxidesolution and with water. Dry the methylene chloride phase over sodiumsulfate and evaporate in vacuo to dryness. Dissolve residue in acetoneand saturate resulting solution with dry hydrogen chloride. Adddiethylether to precipitate the hydrochloride of (c), M.P. 262 to 264.

27 (d) 1-(5-chloro-2methylaminophenyl)-4,4-dimethyl-3,4-

dihydroisoquinoline Add 6.8 parts of (c) to 15 parts by volume ofconcentrated sulfuric acid and leave the resulting mixture for 20 hoursat room temperature. Then pour said mixture on 200 parts of ice and addslowly thereto 30% sodium hydroxide solution until the obtained solutionis weakly basic. Extract resulting mixture three times with 75 parts byvolume of methylene chloride; wash the combined organic phase twice withwater; dry the obtained solution over sodium sulfate and evaporate thesolvent in vacuo. Crystallize the residue by addition thereto of ethanolto obtain ((1), M.P. 125 to 128.

Dissolve 50 parts of 1-(5-chloro-2-methylaminophenyl)-4,4-dimethyl-3,4-dihydroisoquinoline in 500 parts by volume of 95%ethanol and add thereto 5 parts of sodium borohydride. Reflux thethus-obtained mixture for 6 hours; cool; acidify with 2 N hydrochloricacid and evaporate most of the ethanol in vacuo. Add to the concentratesufficient (aq.) sodium hydroxide solution to render said concentratealkaline before extracting same twice with ethyl acetate; wash theorganic phase with water and dry same over sodium sulfate. Evaporate thesol-vent in vacuo and crystallize the residue from diethylether/pentaneto obtain (e), M.P. 110 to 112.

(f) 1-(5-chloro-2-methylaminophenyl)-2-carbomethoxymethyl-4-,4-dimethyl-1,2,3,4-tetrahydroisoquinoline H3OCH3 N-CHz-C-O CH Admix parts of 1-(5-chloro-2-methy1aminophenyl)4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline, 7 parts of triethylamineand 10 parts of methyl bromoacetate in 90 parts by volume of ethanol andreflux the obtained admixture for 4 hours. Evaporate the solvent invacuo; dissolve the residue in ethylacetate, wash the organic solutionwith water; dry same over sodium sulfate and then evaporate in vacuo.Filter the thus-obtained crude product through silica gel(benzene-pentane 1:1 as solvent) to obtain (f), M.P. 111 to 113.

(g) l- 5 -chloro-2-methylaminophenyl) -2-carb oxymethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline Heat a mixture of 2 parts of(f), 10 parts by volume of ethanol and 10 parts by volume of 1 N (aq.)sodium hydroxide solution to reflux for one and one half hours. Then addthereto 10 parts by volume of 1 N (aq.) hydrogen chloride solution andcollect the crystals which are formed. Recrystallize from ethanol/ waterto obtain (g), M.P. 212 to 216.

(h) Heat 1 part of (g) for 40 minutes to 205; then cool same to roomtemperature. Add to the thus-cooled material 5 parts by volume ofmethylene chloride to dissolve any solids and then 10 parts by volume ofdiethylether. Store the resulting solution at 0 overnight and collectthe crystals of the title compound, M.P. 190 to 194, which are thusformed.

Example46.5-methyl-2-trifiuoromethyl-5,9,10,14b-tetrahydroisoquino[2,1-d][1,4]benzodiazepin 6(7H) one hydrochloride CH3 F30- (a)1-(2-chloro-S-trifluoromethyl-phenyl)-3 ,4-dihydroisoquinolinehydrochloride Reflux for 5 hours in 8 parts by volume of stannicchloride a solution of 10 parts of phenethylchloride and 13 parts of2-chloro-5-trifluoromethyl-benzonitrile. Add with intense cooling (DryIce/ acetone) to the cooled mixture 25% sodium hydroxide solution untilthe mixture is alkaline. Extract the very cloudy solution three timeswith ethylacetate. Filter the organic phase; wash same With water andsaturated sodium chloride solution; dry over sodium sulfate andevaporate in vacuo. Dissolve the residue in methylene chloride andsaturate with dry hydrogen chloride gas. Addition thereto ofdiethylether and cooling to 0 yields 7.5 parts of crystalline (a), M.P.212 to 214. The compound may be purified by sublimation at and 0.5 mm.pressure.

Replacing the phenethylchloride with an equivalent of eitherm-(fi-chloroethyDtoluene, p-ethoxyphenethylchloride orl-(fl-chloroethyl)-3,4-methylenedioxybenzene results in the preparation,in similar manner, of the hydrochloride of the corresponding compoundXV.

Replacing the 2 chloro 5 trifluoromethylbenzonitrile with an equivalentof either 2,5-dichlorobenzonitrile, 2-

29 bromo--nitrobenzonitrile or 2-ch1oro-S-fiuorobenzonitrile results inthe preparation, in similar manner, of the hydrochloride of thecorresponding compound XV.

(b) 1- (2-methylamino-5 -trifiuoromethyl-phenyl -3,4-dihydroisoquinoline a FaC Heat to 55 to 60 (autoclave) in 500 partsby volume of liquid methylamine a mixture of 35 parts of 1-(2- chloro 5trifluoromethyl phenyl) 3,4 dihydroisoquinoline hydrochloride, 1.7 partsof cuprous chloride and 1.7 parts of copper powder; maintain theresultant at 55 to 60 for 12 hours. Cool the resultant and evaporate themethylamine at room temperature. Treat the thusobtained residue with 500parts by volume of methylene chloride; filter off insoluble material.Wash the organic phase twice with water; dry over sodium sulfate andevaporate in vacuo to obtain 32 parts of light yellow oil, (b).

Replacing the methylamine with an equivalent of either ethylamine orbenzylaminc results in the preparation, in similar manner, of thecorresponding compound XVII. To obtain compounds XVII wherein R is ahydrogen atom, liquid ammonia is employed under the same conditions.

Replacing (a) with either1-(2-bromo-5-trifluoromethylphenyl)-6-unethoXy-3,4-dihydroisoquinolinehydrochloride, 1 (2,5 dichlorophenyl)- 7 methyl 3,4 dihydroisoquinolinehydrochloride or either of the corresponding free bases, results in thepreparation, in similar manner, of the corresponding compound XVH.

(c) 1 (2 methylamino 5 trifiuoromethyl phenyl) 1,2,3,4-tetrahydroisoquinoline CH3 FaC Reflux for two hours in 400 parts byvolume of 95% ethanol a mixture of 30 parts of1-(2-methylamino-5-trifluoromethyl-phenyl)-3,4-dihydroisoquinoline and 8parts of sodium borohydride. Cool the obtained solution and treat samewith 2 N hydrochloric acid to destroy excess sodium borohydride.Alkalize the resultant with 2 N sodium hydroxide solution and distilloff the solvent in vacuo until 100 parts by volume remain. Extract theresultant mixture three times with ethylacetate. Wash the organic phasetwice with saturated sodium chloride solution; dry same over sodiumsulfate and evaporate in vacuo to obtain 12 parts of (c), M.P. 125 to129, crystallized from ethanol.

(d) 1 (2 methylamino 5 trifluoromethyl phenyl)Z-carbethoxymethyl-1,2,3,4-tetrahydroisoquinoline Reflux for five hoursin 30 parts by volume of ethanol a mixture of 1 part of1-(Z-methylamino-S-trifiuorornethylphenyl)-1,2,3,4-tetrahydroisoquinoline,1 part of ethylbromoacetate and 0.7 part of triethylamine. Evaporate thesolvent in vacuo; dissolve the residue in methylene chloride; wash thesolution with water; dry same over sodium sulfate and evaporate invacuo. Distill the oily residue at 130 and 0.5 mm. pressure andcrystallize the distillate from pentane to obtain 1.1 parts of (d), M.P.to 82'.

(e) Add to a solution of 0.1 part of metallic sodium in 200 parts byvolume of absolute Z-methoxy-ethanol 10 parts of 1(2-methylamino-S-trifluoromethyl-phenyl)-2- carbethoxymethyl 1,2,3,4tetrahydroisoquinoline and reflux for one hour. Distill the solvent offin vacuo and dissolve the residue in methylene chloride. Wash theorganic phase twice with water; dry over sodium sulfate and evaporate invacuo to obtain 9.5 parts of alight brown oil. Dissolve the oil inethylacetate and saturate the solution with dry :hydrogen chloride gas.The hydrochloride (title compound) precipitates on cooling and melts at221 to 225".

It is thought that the invention and its advantages will be understoodfrom the foregoing description. Various changes may be made in theintermediates and the final products (including the pharmaceuticallyacceptable acid addition salts of compounds 1) without departing fromthe spirit and scope of the invention or sacrificing its materialadvantages. The starting materials, intermediates, free bases and acidaddition salts' set forth hereinabove are merely illustrativeembodiments.

What is claimed is:

1. A member selected from the group consisting of a 2 X 5 R -10 R 10 R-12 R -13-R -:S,9,10,14btetrahydroisoquino[2,1 d] [1,4]benzodiazepin6(7H) one, a phanmaceutically acceptable acid addition salt thereof andan N -oxide thereof, and wherein X is a member selected from the groupconsisting of a hydrogen atom, halo, nitro, primary amino andtrifluoromethyl;

each of R and R is, independently, a member selected from the groupconsisting of a hydrogen atom, halo, lower alkyl and lower alkoxy or,taken together, methylenedioxy;

each of R and R is a member selected from the group consisting of ahydrogen atom and lower alkyl; and

R is a member selected from the group consisting of a hydrogen atom,lower alkyl, allyl and propargyl.

2. A compound according to claim 1 which is a member selected from thegroup consisting of a 5,9,10,14b-tetrahydroisoquino[2,1 d][1,4]benzodiazepin-6(7H) one and a pharmaceutically acceptable acidaddition salt thereof, and wherein X is a member selected from the groupconsisting of a hydrogen atom, chloro, bromo, nitro, primary amino andtrifluorornethyl; and

each of R and R is, independently, a member selected from the groupconsisting of a hydrogen atom, chloro, bromo, lower alkyl and loweralkoxy.

3. The compound according to claim 2 which is 5,9,10, 14btctrahydroisoquino [2,1-d] [1,4] benzodiazepin 6- (7H)-one.

4. The compound according to claim 2 which is 2- chloro-5,10dimethyl-5,9,10,14b tetrahydroisoquino- [2, l-d] [1,4] benzodiazepin-6(7H) -one.

5. The compound according to claim 2 which is 2- chloro 5,9,10,14btetrahydroisoquino[2,l-d][1,4]benzodiazepin-6(7H)-one.

6. The compound according to claim 2 which is 2- chloro S-ethyl5,9,10,14b tetrahydroisoquino[2,l-d] [1,4] benzodiazepin-6 (7H) -one.

7. The compound according to claim 2 which is2-chloro-5-methyl-5,9,10,14b tetrahydroisoquino[2,1-d] 1,4]bcnzodiazepin-6 7H) -one.

8. The compound according to claim 2 which is 2- chloro-S-methyl5,9,10,14b tetrahydroisoquino[2,l-d] [1,4] benzodiazepin-6(7H)-one.

9. The compound according to claim 2 which is 2- chloro S-methyl12,l3-dimethoxy-5,9,10,14b-tetrahydroisoquino[2,1-d] [1,4]benzdiabepin-6 (7H)-one.

10. The compound according to claim 2 which is 2-chloro-5,l0,l0-trimethyl 5,9,10,14b tetrahydroisoquino [2,l-d]1,4]benzodiazepin-6 (7H) -one.

11. The compound according to claim 2 which is 2- chloro-5,l0 dimethyl5,9,10,14b tetrahydroisoquino [2,l-d] [1,4] benzodiazepin-6 (7H)-one.

12. A compound according to claim 2 which is of the formula wherein n isa positive whole number from 1 to 5, inclusive.

13. The compound according to claim 2 which is 2- nitro S-methyl5,9,10,14b tetrahydroisoquino[2,l-d] [1,4] benzodiazepin-6 (7H -one.

14. The compound according to claim 2 which is 2- nitro 5,9,10,14btetrahydroisoquino[2,1-d][1,4]benzodiazepin-6(7H)-one.

15. An N -oxide according to claim 1 wherein X is a member selected fromthe group consisting of a hydrogen atom, halo, nitro andtrifluoromethyl; each of R and R is a member selected from the groupconsisting of a hydrogen atom, methoxy and, taken wherein each of n, sand t is, independently, one of the integers 1, 2, 3 and 4; and m is aninteger from 1 to 5, inclusive. 18. A compound according to claim 1which is of the formula m-l 2m l (C 11112 n+1) C1 wherein each of n, sand t is, independently, one of the integers l, 2, 3 and 4; and

m is an integer from 1 to 5, inclusive.

19. The compound according to claim 15 which is (+)-2-chloro-5-methyl5,9,10,14b tetrahydroisoquino [2,1-d)] [1,4] benzodiazepin-6 (7H)-one-8-oxide.

20. A compound according to claim 1 which is of the formula (CaHmrH)wherein each of n, s and t is, independently, one of the integers 1,2, 3and 4; and

m is an integer from 1 to 5, inclusive.

21. The compound according to claim 20 which is 2- bromo S-ethyl10-methyl-12,13 dimethoxy-5,9,10,- 14b tetrahydroisoquino[2,1-d][l,4]benzodiazepin 6- (7H)-one-8-oxide.

22. A compound according to claim 1 which is OzN- wherein each of n, sand t is, independently, one of the integers l, 2, 3 and 4; and

m is an integer from 1 to 5, inclusive.

23. The compound according to claim 1 which is 2- nitro-S-methyl10-ethy1 l3-ethoxy-5,9,10,14b-tetrahydroisoquino[2,l-d][l,4[benzodiazepin 6(7H) one 8- oxide.

24. A compound according to claim 1 of the formula wherein each of n, sand t is, independently, one of the integers l, 2, 3 and 4; and

m is an integer from 1 to 5, inclusive.

25. The compound according to claim 1 which is 2-trifluoromet'hyl-S-methyl l0-propyl l2-propoxy-5,9,l0, 14btetrahydroisoquino[2,l d][1,4]benzodiazepin 6 7H) -one-8-oxide,

26. A compound according to claim 1 which is of the 30. A compoundaccOrding to claim 1 which is of the formula formula m1 2m1 Cm-iH2m-1 whr i wherein I h each of s and t is independently one of the integerseach of s and 2 18, independently, one of the integers 1, 2, 3 and 4;and

1, 2, 3 and 4; and m is an integer of from 1 to 5, inclusive. 27. Acompound according to claim 1 which is-of the m is an integer from 1 to5, inclusive. 31. A compound according to claim 1 which is of theformula formula CnHHzuH ml 2m1 aH2a+1)-O wl (c,H2.+1 o O 0 (CzHZt+l) O Nt 2+1)-O N N Cl FsC wherein wherem t each of s and t is, independently,one of the integers each of s and t 1s, lndependently, one of theIntegers 3a 1, 2, 3 and 4;.and

1, 2, and 4; and m is an integer from 1 to 5, inclusive. m 18 an Integerfrom 1 t0 5,111c1u51ve- 32. The compound according to claim 1 which isThe compound according to claim which 13 2-chlor0-5-methyl5,9,10,14b-tetrahydrois0quin0[2,1-d] racemic 2 ch1oro-S,9,10,14btetrahydroisoqulno[2,1-d] [1,4]benZodiaZepin 6(7H) -One 8 oXide; P )-P q33. The compound according to claim 1 which is 29. A compound accordingto claim 1 WhlCh 1s 0f the -3 1 5 methy1 5,9,10,l4b tetrahydmisoquino[21d] formula [1,4] benZodiazepin-6 (7H) -one-8-oxide.'

34. A compound according to claim 2 wherein X is Cm-1H2m1trifluoromethyl.

35. The compound according to claim 34 which is 5-methyl-2-trifluoromethyl-5,9,l0,14b tetrahydroisoquino [2,1-d][1,4]benzodiazepin- 6(7H)-0ne.

36. A compound according to claim 1 wherein each of (C=H25+1)O O(CtH.+1)0

T R and R is, independently, a lower alkyl.

References Cited f UNITED STATES PATENTS N 3,084,155 4/1963 Winthrop etal. 260239.3

HENRY R. IILES, Primary Examiner.

wherein R. T. BOND, Assistant Examiner.

each of s and t is, independently, one of the integers Us. CL XR 1, 2, 3and 4; and m is an integer from 1 to 5, inclusive. 260283, 287, 288;424-258

